Hydroisoindoline tachykinin receptor antagonists

ABSTRACT

The present invention is directed to certain hydroisoindoline compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, urinary incontinence, depression, and anxiety.

BACKGROUND OF THE INVENTION

Substance P is a naturally occurring undecapeptide belonging to thetachykinin family of peptides, the latter being so-named because oftheir prompt contractile action on extravascular smooth muscle tissue.The tachykinins are distinguished by a conserved carboxyl-terminalsequence. In addition to substance P, the known mammalian tachykininsinclude neurokinin A and neurokinin B. The current nomenclaturedesignates the receptors for substance P, neurokinin A, and neurokinin Bas neurokinin-1 (NK-1), neurokinin-2 (NK-2), and neurokinin-3 (NK-3),respectively.

Tachykinin, and in particular substance P, antagonists are useful in thetreatment of clinical conditions which are characterized by the presenceof an excess of tachykinin, in particular substance P, activity,including disorders of the central nervous system, nociception and pain,gastrointestinal disorders, disorders of bladder function andrespiratory diseases.

SUMMARY OF THE INVENTION

The present invention is directed to certain hydroisoindoline compoundswhich are useful as neurokinin-1 (NK-1) receptor antagonists, andinhibitors of tachykinin and in particular substance P. The invention isalso concerned with pharmaceutical formulations comprising thesecompounds as active ingredients and the use of the compounds and theirformulations in the treatment of certain disorders, including emesis,urinary incontinence, depression, and anxiety.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:R¹ is selected from the group consisting of:

(1) hydrogen,

(2) C₁₋₆alkyl, which is unsubstituted or substituted with halogen,hydroxyl or phenyl,

(3) cyclopentenone, which is unsubstituted or substituted with hydroxylor methyl,

(4) —(CO)—C₁₋₆alkyl,

(5) —(CO)—NH₂,

(6) —(CO)—NHC₁₋₆alkyl, and

(7) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl);

X is independently selected from the group consisting of:

(1) hydrogen,

(2) fluorine, and

(3) methyl;

and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein R¹ and X are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R¹ and X are defined herein;and pharmaceutically acceptable salts thereof and individual enantiomersand diastereomers thereof.

An embodiment of the present invention includes compounds wherein R¹ isselected from the group consisting of:

(1) hydrogen,

(2) C₁₋₃alkyl, which is unsubstituted or substituted with hydroxyl orphenyl,

(3) cyclopent-2-en-1-one, which is unsubstituted or substituted withhydroxyl or methyl,

(4) —(CO)—C₁₋₃alkyl,

(5) —(CO)—NH₂,

(6) —(CO)—NHC₁₋₃alkyl, and

(7) —(CO)—N(C₁₋₃alkyl)(C₁₋₃alkyl).

Within this embodiment the present invention includes compounds whereinR¹ is selected from the group consisting of:

(1) hydrogen,

(2) methyl,

(3) 2-phenylethyl,

(4) 2-hydroxyethyl,

(5) cyclopent-2-en-1-one,

(6) 5-hydroxycyclopent-2-en-1-one,

(7) 4-hydroxycyclopent-2-en-1-one,

(8) 2-methylcyclopent-2-en-1-one,

(9) acetyl,

(10) acetamido,

(11) methyl-acetamido, and

(12) dimethyl-acetamido.

Further within this embodiment, the present invention is directed tocompounds wherein R¹ is hydrogen.

Also further within this embodiment, the present invention is directedto compounds wherein R¹ is methyl, 2-phenylethyl or 2-hydroxyethyl.

Also further within this embodiment, the present invention is directedto compounds wherein R¹ is:

which is unsubstituted or substituted with hydroxyl or methyl.

Also further within this embodiment, the present invention is directedto compounds wherein R¹ is acetyl, acetamido, methyl-acetamido ordimethyl-acetamido.

An embodiment of the present invention includes compounds wherein X ishydrogen. An embodiment of the present invention includes compoundswherein X is fluorine. An embodiment of the present invention includescompounds wherein X is methyl.

Specific embodiments of the present invention include a compound whichis selected from the group consisting of the subject compounds of theExamples herein and pharmaceutically acceptable salts thereof andindividual enantiomers and diastereomers thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Formula I showsthe structure of the class of compounds without preferredstereochemistry. The independent syntheses of these diastereomers ortheir chromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

There are several acceptable methods of naming the compounds discussedherein.

For example, the above compound can be named either as “(3aR,4R,5S,7aR)tert-butyl-5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate” or“tert-butyl(3aR,4R,5S,7aR)-5-hydroxy-4-phenyloctahydro-2H-isoindole-2-carboxylate”.The core structure may be generally referred to as octahydroisoindole,hexahydroisoindoline, perhydroisoindoline, hydroisoindoline, orhydroisoindole compounds.

As appreciated by those of skill in the art, halo or halogen as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₈alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. A groupwhich is designated as being independently substituted with substituentsmay be independently substituted with multiple numbers of suchsubstituents.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts in thesolid form may exist in more than one crystal structure, and may also bein the form of hydrates. Salts derived from pharmaceutically acceptableorganic non-toxic bases include salts of primary, secondary, andtertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines, and basic ion exchange resins, suchas arginine, betaine, caffeine, choline, N,N′-dibenzylethylene-diamine,diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol,ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine, and the like. When the compound of thepresent invention is basic, salts may be prepared from pharmaceuticallyacceptable non-toxic acids, including inorganic and organic acids. Suchacids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particularly preferred are citric,hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, andtartaric acids. It will be understood that, as used herein, referencesto the compounds of the present invention are meant to also include thepharmaceutically acceptable salts.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual diastereomers thereof.

The compounds of the present invention are useful in the prevention andtreatment of a wide variety of clinical conditions which arecharacterized by the presence of an excess of tachykinin, in particularsubstance P, activity. Thus, for example, an excess of tachykinin, andin particular substance P, activity is implicated in a variety ofdisorders of the central nervous system. Such disorders include mooddisorders, such as depression or more particularly depressive disorders,for example, single episodic or recurrent major depressive disorders anddysthymic disorders, or bipolar disorders, for example, bipolar Idisorder, bipolar II disorder and cyclothymic disorder; anxietydisorders, such as panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobias, forexample, specific animal phobias, social phobias, obsessive-compulsivedisorder, stress disorders including post-traumatic stress disorder andacute stress disorder, and generalised anxiety disorders; schizophreniaand other psychotic disorders, for example, schizophreniform disorders,schizoaffective disorders, delusional disorders, brief psychoticdisorders, shared psychotic disorders and psychotic disorders withdelusions or hallucinations; delirium, dementia, and amnestic and othercognitive or neurodegenerative disorders, such as Alzheimer's disease,senile dementia, dementia of the Alzheimer's type, vascular dementia,and other dementias, for example, due to HIV disease, head trauma,Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jakob disease, or due to multiple aetiologies; Parkinson'sdisease and other extra-pyramidal movement disorders such asmedication-induced movement disorders, for example, neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor;substance-related disorders arising from the use of alcohol,amphetamines (or amphetamine-like substances) caffeine, cannabis,cocaine, hallucinogens, inhalants and aerosol propellants, nicotine,opioids, phenylglycidine derivatives, sedatives, hypnotics, andanxiolytics, which substance-related disorders include dependence andabuse, intoxication, withdrawal, intoxication delirium, withdrawaldelirium, persisting dementia, psychotic disorders, mood disorders,anxiety disorders, sexual dysfunction and sleep disorders; epilepsy;Down's syndrome; demyelinating diseases such as MS and ALS and otherneuropathological disorders such as peripheral neuropathy, for examplediabetic and chemotherapy-induced neuropathy, and postherpeticneuralgia, trigeminal neuralgia, segmental or intercostal neuralgia andother neuralgias; and cerebral vascular disorders due to acute orchronic cerebrovascular damage such as cerebral infarction, subarachnoidhaemorrhage or cerebral oedema.

Tachykinin, and in particular substance P, activity is also involved innociception and pain. The compounds of the present invention willtherefore be of use in the prevention or treatment of diseases andconditions in which pain predominates, including soft tissue andperipheral damage, such as acute trauma, osteoarthritis, rheumatoidarthritis, musculo-skeletal pain, particularly after trauma, spinalpain, myofascial pain syndromes, headache, episiotomy pain, and burns;deep and visceral pain, such as heart pain, muscle pain, eye pain,orofacial pain, for example, odontalgia, abdominal pain, gynaecologicalpain, for example, dysmenorrhoea, and labour pain; pain associated withnerve and root damage, such as pain associated with peripheral nervedisorders, for example, nerve entrapment and brachial plexus avulsions,amputation, peripheral neuropathies, tic douloureux, atypical facialpain, nerve root damage, and arachnoiditis; pain associated withcarcinoma, often referred to as cancer pain; central nervous systempain, such as pain due to spinal cord or brain stem damage; low backpain; sciatica; ankylosing spondylitis, gout; and scar pain.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of respiratory diseases, particularly thoseassociated with excess mucus secretion, such as chronic obstructiveairways disease, bronchopneumonia, chronic bronchitis, cystic fibrosisand asthma, adult respiratory distress syndrome, and bronchospasm;inflammatory diseases such as inflammatory bowel disease, psoriasis,fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn;allergies such as eczema and rhinitis; hypersensitivity disorders suchas poison ivy; ophthalmic diseases such as conjunctivitis, vernalconjunctivitis, and the like; ophthalmic conditions associated with cellproliferation such as proliferative vitreoretinopathy; cutaneousdiseases such as contact dermatitis, atopic dermatitis, urticaria, andother eczematoid dermatitis. Tachykinin, and in particular substance P,antagonists may also be of use in the treatment of neoplasms, includingbreast tumours, neuroganglioblastomas and small cell carcinomas such assmall cell lung cancer.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of gastrointestinal (GI) disorders, includinginflammatory disorders and diseases of the GI tract such as gastritis,gastroduodenal ulcers, gastric carcinomas, gastric lymphomas, disordersassociated with the neuronal control of viscera, ulcerative colitis,Crohn's disease, irritable bowel syndrome and emesis, including acute,delayed or anticipatory emesis such as emesis induced by chemotherapy,radiation, toxins, viral or bacterial infections, pregnancy, vestibulardisorders, for example, motion sickness, vertigo, dizziness andMeniere's disease, surgery, migraine, variations in intercranialpressure, gastro-oesophageal reflux disease, acid indigestion, overindulgence in food or drink, acid stomach, waterbrash or regurgitation,heartburn, for example, episodic, nocturnal or meal-induced heartburn,and dyspepsia.

Tachykinin, and in particular substance P, antagonists may also be ofuse in the treatment of a variety of other conditions including stressrelated somatic disorders; reflex sympathetic dystrophy such asshoulder/hand syndrome; adverse immunological reactions such asrejection of transplanted tissues and disorders related to immuneenhancement or suppression such as systemic lupus erythematosus; plasmaextravasation resulting from cytokine chemotherapy, disorders of bladderfunction such as cystitis, bladder detrusor hyper-reflexia, frequenturination and urinary incontinence, including the prevention ortreatment of overactive bladder with symptoms of urge urinaryincontinence, urgency, and frequency; fibrosing and collagen diseasessuch as scleroderma and eosinophilic fascioliasis; disorders of bloodflow caused by vasodilation and vasospastic diseases such as angina,vascular headache, migraine and Reynaud's disease; and pain ornociception attributable to or associated with any of the foregoingconditions, especially the transmission of pain in migraine. Thecompounds of the present invention are also of value in the treatment ofa combination of the above conditions, in particular in the treatment ofcombined post-operative pain and post-operative nausea and vomiting.

The compounds of the present invention are particularly useful in theprevention or treatment of emesis, including acute, delayed oranticipatory emesis, such as emesis induced by chemotherapy, radiation,toxins, pregnancy, vestibular disorders, motion, surgery, migraine, andvariations in intercranial pressure. For example, the compounds of thepresent invention are of use optionally in combination with otherantiemetic agents for the prevention of acute and delayed nausea andvomiting associated with initial and repeat courses of moderate orhighly emetogenic cancer chemotherapy, including high-dose cisplatin.Most especially, the compounds of the present invention are of use inthe treatment of emesis induced by antineoplastic (cytotoxic) agents,including those routinely used in cancer chemotherapy, and emesisinduced by other pharmacological agents, for example, rolipram. Examplesof such chemotherapeutic agents include alkylating agents, for example,ethyleneimine compounds, alkyl sulphonates and other compounds with analkylating action such as nitrosoureas, cisplatin and dacarbazine;antimetabolites, for example, folic acid, purine or pyrimidineantagonists; mitotic inhibitors, for example, vinca alkaloids andderivatives of podophyllotoxin; and cytotoxic antibiotics. Particularexamples of chemotherapeutic agents are described, for instance, by D.J. Stewart in Nausea and Vomiting: Recent Research and ClinicalAdvances, Eds. J. Kucharczyk et al, CRC Press Inc., Boca Raton, Fla.,USA (1991) pages 177-203, especially page 188. Commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine, streptozocin, cyclophosphamide,carmustine (BCNU), lomustine (CCNU), doxorubicin (adriamycin),daunorubicin, procarbazine, mitomycin, cytarabine, etoposide,methotrexate, 5-fluorouracil, vinblastine, vincristine, bleomycin andchlorambucil [R. J. Gralla et al in Cancer Treatment Reports (1984)68(1), 163-172]. A further aspect of the present invention comprises theuse of a compound of the present invention for achieving achronobiologic (circadian rhythm phase-shifting) effect and alleviatingcircadian rhythm disorders in a mammal. The present invention is furtherdirected to the use of a compound of the present invention for blockingthe phase-shifting effects of light in a mammal.

The present invention is further directed to the use of a compound ofthe present invention or a pharmaceutically acceptable salt thereof, forenhancing or improving sleep quality as well as preventing and treatingsleep disorders and sleep disturbances in a mammal. In particular, thepresent invention provides a method for enhancing or improving sleepquality by increasing sleep efficiency and augmenting sleep maintenance.In addition, the present invention provides a method for preventing andtreating sleep disorders and sleep disturbances in a mammal whichcomprising the administration of a compound of the present invention ora pharmaceutically acceptable salt thereof. The present invention isuseful for the treatment of sleep disorders, including Disorders ofInitiating and Maintaining Sleep (insomnias) (“DIMS”) which can arisefrom psychophysiological causes, as a consequence of psychiatricdisorders (particularly related to anxiety), from drugs and alcohol useand abuse (particularly during withdrawal stages), childhood onset DIMS,nocturnal myoclonus, fibromyalgia, muscle pain, sleep apnea and restlesslegs and non specific REM disturbances as seen in aging.

The particularly preferred embodiments of the instant invention are thetreatment of emesis, urinary incontinence, depression or anxiety byadministration of the compounds of the present invention to a subject(human or animal) in need of such treatment.

The present invention is directed to a method for the manufacture of amedicament for antagonizing the effect of substance P at its receptorsite or for the blockade of neurokinin-1 receptors in a mammalcomprising combining a compound of the present invention with apharmaceutical carrier or diluent. The present invention is furtherdirected to a method for the manufacture of a medicament for thetreatment of a physiological disorder associated with an excess oftachykinins in a mammal comprising combining a compound of the presentinvention with a pharmaceutical carrier or diluent.

The present invention also provides a method for the treatment orprevention of physiological disorders associated with an excess oftachykinins, especially substance P, which method comprisesadministration to a patient in need thereof of a tachykinin reducingamount of a compound of the present invention or a compositioncomprising a compound of the present invention. As used herein, the term“treatment” or “to treat” refers to the administration of the compoundsof the present invention to reduce, ameliorate, or eliminate either thesymptoms or underlying cause of the noted disease conditions, in asubject (human or animal) that suffers from that condition or displaysclinical indicators thereof. The term “prevention” or “to prevent”refers to the administration of the compounds of the present inventionto reduce, ameliorate, or eliminate the risk or likelihood of occurrenceof the noted disease conditions, in a subject (human or animal)susceptible or predisposed to that condition.

The compounds of this invention are useful for antagonizing tachykinins,in particular substance P in the treatment of gastrointestinaldisorders, central nervous system disorders, inflammatory diseases, painor migraine and asthma in a mammal in need of such treatment. Thisactivity can be demonstrated by the following assays.

Receptor Expression in COS: To express the cloned human neurokinin-1receptor (NK1R) transiently in COS, the cDNA for the human NK1R wascloned into the expression vector pCDM9 which was derived from pCDM8(INVITROGEN) by inserting the ampicillin resistance gene (nucleotide1973 to 2964 from BLUESCRIPT SK+) into the Sac II site. Transfection of20 ug of the plasmid DNA into 10 million COS cells was achieved byelectroporation in 800 ul of transfection buffer (135 mM NaCl, 1.2 mMCaCl₂, 1.2 mM MgCl₂, 2.4 mM K₂HPO₄, 0.6 mM KH₂PO₄, 10 mM glucose, 10 mMHEPES pH 7.4) at 260 V and 950 uF using the IBI GENEZAPPER (IBI, NewHaven, Conn.). The cells were incubated in 10% fetal calf serum, 2 mMglutamine, 100 U/ml penicillin-streptomycin, and 90% DMEM media (GIBCO,Grand Island, N.Y.) in 5% CO₂ at 37° C. for three days before the assay.

Stable Expression in CHO: To establish a stable cell line expressing thecloned human NK1R, the cDNA was subcloned into the vector pRcCMV(INVITROGEN). Transfection of 20 ug of the plasmid DNA into CHO cellswas achieved by electroporation in 800 ul of transfection buffersupplemented with 0.625 mg/ml Herring sperm DNA at 300 V and 950 uFusing the IBI GENEZAPPER (IBI). The transfected cells were incubated inCHO media [10% fetal calf serum, 100 U/ml penicillin-streptomycin, 2 mMglutamine, 1/500 hypoxanthine-thymidine (ATCC), 90% IMDM media (JRHBIOSCIENCES, Lenexa, Kans.), 0.7 mg/ml G418 (GIBCO)] in 5% CO₂ at 37° C.until colonies were visible. Each colony was separated and propagated.The cell clone with the highest number of human NK1R was selected forsubsequent applications such as drug screening.

Assay Protocol using COS or CHO: The binding assay of human NK1Rexpressed in either COS or CHO cells is based on the use of¹²⁵I-substance P (¹²⁵I—SP, from DU PONT, Boston, Mass.) as aradioactively labeled ligand which competes with unlabeled substance Por any other ligand for binding to the human NK1R. Monolayer cellcultures of COS or CHO were dissociated by the non-enzymatic solution(SPECIALTY MEDIA, Lavallette, N.J.) and resuspended in appropriatevolume of the binding buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mMNaCl, 0.04 mg/ml bacitracin, 0.004 mg/ml leupeptin, 0.2 mg/ml BSA, 0.01mM phosphoramidon) such that 200 ul of the cell suspension would giverise to about 10,000 cpm of specific ¹²⁵I—SP binding (approximately50,000 to 200,000 cells). In the binding assay, 200 ul of cells wereadded to a tube containing 20 ul of 1.5 to 2.5 nM of ¹²⁵I—SP and 20 ulof unlabeled substance P or any other test compound. The tubes wereincubated at 4° C. or at room temperature for 1 hour with gentleshaking. The bound radioactivity was separated from unboundradioactivity by GF/C filter (BRANDEL, Gaithersburg, Md.) which waspre-wetted with 0.1% polyethylenimine. The filter was washed with 3 mlof wash buffer (50 mM Tris pH 7.5, 5 mM MnCl₂, 150 mM NaCl) three timesand its radioactivity was determined by gamma counter. The activation ofphospholipase C by NK1R may also be measured in CHO cells expressing thehuman NK1R by determining the accumulation of inositol monophosphatewhich is a degradation product of IP₃. CHO cells are seeded in 12-wellplate at 250,000 cells per well. After incubating in CHO media for 4days, cells are loaded with 0.025 uCi/ml of ³H-myoinositol by overnightincubation. The extracellular radioactivity is removed by washing withphosphate buffered saline. LiCl is added to the well at finalconcentration of 0.1 mM with or without the test compound, andincubation is continued at 37° C. for 15 min. Substance P is added tothe well at final concentration of 0.3 nM to activate the human NK1R.After 30 min of incubation at 37° C., the media is removed and 0.1 N HClis added. Each well is sonicated at 4° C. and extracted withCHCl₃/methanol (1:1). The aqueous phase is applied to a 1 ml Dowex AG1×8 ion exchange column. The column is washed with 0.1 N formic acidfollowed by 0.025 M ammonium formate-0.1 N formic acid. The inositolmonophosphate is eluted with 0.2 M ammonium formate-0.1 N formic acidand quantitated by beta counter. In particular, the intrinsic tachykininreceptor antagonist activities of the compounds of the present inventionmay be demonstrated by these assays. The compounds of the followingexamples have activity in the aforementioned assays in the range of 0.05nM to 10 μM. The activity of the present compounds may also bedemonstrated by the assay disclosed by Lei, et al., British J.Pharmacol., 105, 261-262 (1992).

According to a further or alternative aspect, the present inventionprovides a compound of the present invention for use as a compositionthat may be administered to a subject in need of a reduction of theamount of tachykinin or substance P in their body.

The term “composition” as used herein is intended to encompass a productcomprising specified ingredients in predetermined amounts orproportions, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts. This term in relation to pharmaceutical compositionsis intended to encompass a product comprising one or more activeingredients, and an optional carrier comprising inert ingredients, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. In general, pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives.

Pharmaceutical compositions of the present compounds may be in the formof a sterile injectable aqueous or oleagenous suspension. The compoundsof the present invention may also be administered in the form ofsuppositories for rectal administration. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention may be employed. The compounds of thepresent invention may also be formulated for administered by inhalation.The compounds of the present invention may also be administered by atransdermal patch by methods known in the art.

The compositions containing compounds of the present invention may bepresented in unit dosage form and may be prepared by any of the methodswell known in the art of pharmacy. The term “unit dosage form” is takento mean a single dose wherein all active and inactive ingredients arecombined in a suitable system, such that the patient or personadministering the drug to the patient can open a single container orpackage with the entire dose contained therein, and does not have to mixany components together from two or more containers or packages. Typicalexamples of unit dosage forms are tablets or capsules for oraladministration, single dose vials for injection, or suppositories forrectal administration. This list of unit dosage forms is not intended tobe limiting in any way, but merely to represent typical examples in thepharmacy arts of unit dosage forms. The compositions containingcompounds of the present invention may also be presented as a kit,whereby two or more components, which may be active or inactiveingredients, carriers, diluents, and the like, are provided withinstructions for preparation of the actual dosage form by the patient orperson administering the drug to the patient. Such kits may be providedwith all necessary materials and ingredients contained therein, or theymay contain instructions for using or making materials or componentsthat must be obtained independently by the patient or personadministering the drug to the patient.

By “pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

The terms “administration of” or “administering a” compound should beunderstood to mean providing a compound of the invention to theindividual in need of treatment in a form that can be introduced intothat individuals body in a therapeutically useful form andtherapeutically effective amount, including, but not limited to: oraldosage forms, such as tablets, capsules, syrups, suspensions, and thelike; injectable dosage forms, such as IV, IM, or IP, and the like;transdermal dosage forms, including creams, jellies, powders, orpatches; buccal dosage forms; inhalation powders, sprays, suspensions,and the like; and rectal suppositories. The term “therapeuticallyeffective amount” refers to a sufficient quantity of the compounds ofthe present invention, in a suitable composition, and in a suitabledosage form to treat or prevent the noted disease conditions.

The compounds of the present invention may be administered incombination with another substance that has a complimentary effect tothe tachykinin and substance P inhibitors of the present invention.Accordingly, in the prevention or treatment of emesis, a compound of thepresent invention may be used in conjunction with other anti-emeticagents, especially 5HT₃ receptor antagonists, such as ondansetron,granisetron, tropisetron, palenosetron and zatisetron, a corticosteroid,such as dexamethasone, or GABA_(B) receptor agonists, such as baclofen.Likewise, for the prevention or treatment of migraine a compound of thepresent invention may be used in conjunction with other anti-migraineagents, such as ergotamines or 5HT₁ agonists, especially sumatriptan,naratriptan, zolmatriptan or rizatriptan.

It will be appreciated that for the treatment of depression or anxiety,a compound of the present invention may be used in conjunction withother anti-depressant or anti-anxiety agents, such as norepinephrinereuptake inhibitors, selective serotonin reuptake inhibitors (SSRIs),monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamineoxidase (RIMAs), serotonin and noradrenaline reuptake inhibitors(SNRIs), α-adrenoreceptor antagonists, atypical anti-depressants,benzodiazepines, 5-HT_(1A) agonists or antagonists, especially 5-HT_(1A)partial agonists, corticotropin releasing factor (CRF) antagonists, andpharmaceutically acceptable salts thereof. For the treatment orprevention of eating disorders, including obesity, bulimia nervosa andcompulsive eating disorders, a compound of the present invention may beused in conjunction with other anorectic agents. It will be appreciatedthat for the treatment or prevention of pain or nociception orinflammatory diseases, a compound of the present invention may be usedin conjunction with an antiinflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, such as an inhibitor of5-lipoxygenase, a cyclooxygenase inhibitor, such as a cyclooxygenase-2inhibitor, an interleukin inhibitor, such as an interleukin-1 inhibitor,an NMDA antagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal antiinflammatory agent, or acytokine-suppressing antiinflammatory agent.

It will be appreciated that when using any combination described herein,both the compound of the present invention and the other active agent(s)will be administered to a patient, within a reasonable period of time.The compounds may be in the same pharmaceutically acceptable carrier andtherefore administered simultaneously. They may be in separatepharmaceutical carriers such as conventional oral dosage forms which aretaken simultaneously. The term “combination” also refers to the casewhere the compounds are provided in separate dosage forms and areadministered sequentially. Therefore, by way of example, one activecomponent may be administered as a tablet and then, within a reasonableperiod of time, the second active component may be administered eitheras an oral dosage form such as a tablet or a fast-dissolving oral dosageform. By a “fast dissolving oral formulation” is meant, an oral deliveryform which when placed on the tongue of a patient, dissolves withinabout 10 seconds. By “reasonable period of time” is meant a time periodthat is not in excess of about 1 hour. That is, for example, if thefirst active component is provided as a tablet, then within one hour,the second active component should be administered, either in the sametype of dosage form, or another dosage form which provides effectivedelivery of the medicament.

The compounds of this invention may be administered to patients (animalsand humans) in need of such treatment in dosages that will provideoptimal pharmaceutical efficacy. It will be appreciated that the doserequired for use in any particular application will vary from patient topatient, not only with the particular compound or composition selected,but also with the route of administration, the nature of the conditionbeing treated, the age and condition of the patient, concurrentmedication or special diets then being followed by the patient, andother factors which those skilled in the art will recognize, with theappropriate dosage ultimately being at the discretion of the attendantphysician.

In the treatment of the conditions associated with an excess oftachykinins, a suitable dosage level of the compounds of the presentinvention, or pharmaceutically acceptable salts thereof, is about 0.001to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such asfrom about 0.05 to about 10 mg/kg per day. The dosage range willgenerally be about 0.5 to 1000 mg per patient per day, which may beadministered in single or multiple doses. Preferably, the dosage rangewill be about 0.5 mg to 500 mg per patient per day; more preferablyabout 0.5 mg to 200 mg per patient per day; and even more preferablyabout 5 mg to 50 mg per patient per day. Specific dosages of thecompounds of the present invention, or pharmaceutically acceptable saltsthereof, for administration include 1 mg, 5 mg, 10 mg, 30 mg, 100 mg,and 500 mg. Pharmaceutical compositions of the present invention may beprovided in a formulation comprising about 0.5 mg to 1000 mg activeingredient; more preferably comprising about 0.5 mg to 500 mg activeingredient; or 0.5 mg to 250 mg active ingredient; or 1 mg to 100 mgactive ingredient. Specific pharmaceutical compositions for treatment orprevention of excess tachykinins comprise about 1 mg, 5 mg, 10 mg, 30mg, 100 mg, and 500 mg of active ingredient.

Several methods for preparing the compounds of this invention areillustrated in the following Examples. Starting materials and therequisite intermediates are in some cases commercially available, or canbe prepared according to literature procedures or as illustrated herein.All ¹H NMR spectra were obtained on instrumentation at a field strengthof 400 or 500 MHz.

EXAMPLE 1

(3aR,4R,5S,7aR)-5-{1(S)-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindoleand(3aS,4S,5R,7aS)-5-{1(S)-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-1H-isoindoleStep A: 2-(4-Fluorophenyl)-N-methoxy-N-methylacetamide

To a solution of 16.7 g (108.4 mmol) (4-fluorophenyl)acetic acid in drymethylene chloride under nitrogen atmosphere was added 13.8 g (141.5mmol) N,O-dimethyl-hydroxylamine, 20 mL triethylamine, 14.2 g (119.3mmol) 4-dimethylaminopyridine (DMAP) and 27 g (140.6 mmol) EDC. Thereaction mixture was stirred at RT for 2 hr then transferred to aseparatory funnel. The mixture was washed consecutively with 2 N aq.HCl, brine, saturated aq. NaHCO₃ and brine. The organic layer was driedover drying agent, filtered and the solvent evaporated under vacuum togive 21 g of the crude title compound which was used without furtherpurification. ¹H-NMR (CDCl₃): δ: 7.26 (2H, m), 7.02 (2H, m), 3.77 (2H,s), 3.65 (3H, s), 3.21 (3H, s).

Step B: 1-(4-Fluorophenyl)but-3-en-2-one

To a solution of 220 mL (1.0 M, 220 mmol) of vinylmagnesium bromide in100 mL THF, was added dropwise under nitrogen atmosphere at 0° C. asolution of 21 g (106.6 mmol)2-(4-fluoro-phenyl)-N-methoxy-N-methylacetamide (step A) in 150 mL dryether. The reaction mixture was stirred at 0° C. for 0.5 hr then pouredslowly into an ice/2N aq HCl mixture. The resulting mixture was dilutedwith ether and brine, transferred to a separatory funnel and the organiclayer separated. The organic layer was washed with brine, dried overdrying agent, filtered and the solvent evaporated under vacuum to give14.2 g of the crude title compound which was used without furtherpurification. ¹H-NMR (CDCl₃): δ: 7.19 (2H, m), 7.02 (2H, t, J=9.5 Hz),6.42 (1H, dd, J=14.2 Hz, J₂=11 Hz), 6.34 (1H, d, J=14.2 Hz), 5.86 (1H,d, J=11 Hz), 3.87 (2H, s).

Step C: 1E and 1Ztert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane

To a solution of 104 mL (104.0 mmol, 1.2 equiv.) of a 1.0M solution ofpotassium tert-butoxide in THF and 100 mL dry THF under nitrogenatmosphere at −78° C. was added a solution of 14.2 g (86.6 mmol, 1equiv.) of 1-(4-fluorophenyl)but-3-en-2-one (step B) and 13.0 g (86.6mmol) tert-butylchlorodimethylsilane in 100 mL dry THF. The reactionmixture was stirred at −78° C. for 6 hr and at RT for 6 hr then quenchedby the addition of 50 mL water. The resulting mixture was warmed to RT,diluted with 150 mL hexanes, transferred to a separatory funnel and theorganic layer separated. The organic layer was washed with 50 mL brine,dried over anhydrous magnesium sulfate, filtered and the solventevaporated under vacuum to give 20.5 g of the crude title compoundswhich were used without further purification. ¹H-NMR (CDCl₃): δ: 7.52(2H, m), 6.98 (2H, m), 6.33 (1H, dd, J₁=13.2 Hz, J₂=8.5 Hz), 5.97 (1H,s), 5.52 (1H, d, J=13.2 Hz), 5.17 (1H, d, J=8.5 Hz).

Step D:(3aS,4R,7aR)-2-benzyl-5-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-fluorophenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dioneand(3aR,4S,7aS)-2-benzyl-5-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-fluorophenyl)-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione

A solution of 15 g (54.0 mmol, 1 equiv.) of 1E and 1Ztert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane(step C) and 12.1 g (64.6 mmol) N-benzylmaleimide in 150 mL dry tolueneunder nitrogen atmosphere was heated at reflux for 16 hr then cooled toRT. The solvent evaporated under vacuum to give 31 g of the crude titlecompounds which contained the unreacted N-benzylmaleimide and were usedwithout further purification. ¹H-NMR (CDCl₃): δ: 7.37-7.26 (3H, m), 7.22(2H, m), 7.00 (2H, m), 6.78 (2H, t, J=8.5 Hz), 5.07 (1H, t, J=2.3 Hz),4.22 (1H, d, J=16 Hz), 4.15 (1H, d, J=16 Hz), 3.66 (1H, d, J=6.5 Hz),3.52 (1H, t, J=7.0 Hz), 3.14 (1H, m), 2.87 (1H, m), 2.68 (1H, m), 0.92(1H, m), 0.78 (9H, s), 0.11 (3H, s), −0.1 (3H, s).

Step E:(3aS,4S,7aS)-2-benzyl-5-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-fluorophenyl)-2,3,3a,4,7,7a-hexahydro-1H-isoindoleand(3aR,4R,7aR)-2-benzyl-5-{[tert-butyl(dimethyl)silyl]oxy}-4-(4-fluorophenyl)-2,3,3a,4,7,7a-hexahydro-1H-isoindole

In a round bottom flask was added 7.3 g (192.0 mmol, excess) lithiumaluminium hydride in dry ether under nitrogen atmosphere at 0° C. To theresulting mixture was added dropwise a solution of 31 g of the crudeintermediate of step D in 100 mL dry methylene chloride under nitrogenatmosphere. The resulting mixture was stirred at RT for 1 hr thencarefully quenched at 0° C. by the dropwise addition of 12 mL water,then 10 mL 5.0 N aq. NaOH. The resulting suspension was stirred at RTfor 0.5 hr and the solids filtered. The solvent of the filtrate wasevaporated under vacuum to give the crude title compounds which wereused without further purification.

Step F:(3aS,4S,7aS)-2-benzyl-4-(4-fluorophenyl)octahydro-5H-isoindol-5-one and(3aR,4R,7aR)-2-benzyl-4-(4-fluorophenyl)octahydro-5H-isoindol-5-one

To a solution of the intermediate of step E in 60 mL dry acetonitrileunder nitrogen atmosphere at RT was added 100 mL (250 mmol) of a 2.5 Msolution of HF in acetonitrile. The resulting mixture was stirred at RTfor 16 hr then quenched at 0° C. by the dropwise addition of 120 mL 5.0N aq. NaOH. The acetonitrile was evaporated under vacuum and theresulting aqueous mixture was diluted with ether and water. Theresulting mixture was transferred to a separatory funnel and the organiclayer separated. The aqueous layer was extracted with an additionalportion of ether. The combined organic layers were washed with 50 mLbrine, dried over drying agent, filtered and the solvent evaporatedunder vacuum. The residue was purified by flash column chromatography onsilica gel eluting with EtOAc/hexanes (1/1) to give 9.0 g of the racemictitle compounds. ¹H-NMR (CDCl₃): δ: 7.27-7.23 (3H, m), 7.12-7.03 (2H,m), 3.75 (1H, d, J=12.9 Hz), 3.61 (2H, d, J=4.8 Hz), 3.61 (1H, q, J=14.5Hz), 2.93 (1H, t, J=8.5 Hz), 2.68-2.52 (3H, m), 2.43-2.33 (2H, m), 2.25(1H, m), 2.05 (2H, m).

Step G:(3aS,4S,5R,7aS)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-oland(3aR,4R,5S,7aR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol

To a solution of the intermediate (9.0 g) of step F under nitrogenatmosphere in dry ether at −78° C. was added a 1.0M solution of lithiumaluminium hydride (38.3 mL) in ether. The resulting mixture was stirredat −78° C. for 0.5 hr then carefully quenched by the dropwise additionof water, then 5.0 N aq. NaOH. The resulting suspension was stirred atRT for 0.5 hr and the solids filtered. The solvent of the filtrate wasevaporated under vacuum to give the crude title compounds as the majorcompounds which were used without further purification. ¹H-NMR (CDCl₃):δ: 7.38-7.20 (7H, m), 7.05 (2H, t, J=8.5 Hz), 3.75 (2H, s), 3.75 (1H,m), 2.8-2.65 (4H, m), 2.60 (1H, m), 2.50 (1H, m), 2.38 (1H, d, J=8.1Hz), 2.21 (1H, m), 1.95 (1H, m), 1.81 (2H, m), 1.73-1.62 (2H, m). MS:(MH)⁺ 261.9.

Step H: (3aS,4S,5R,7aS)-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol and(3aR,4R,5S,7aR)-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol

The intermediate of step G was hydrogenated at 50 PSI hydrogen over 10%by weight of 10% Pd—C in ethanol for 16 hr at RT. The catalyst wasfiltered and the solvent of the filtrate was evaporated under vacuum togive the crude title compounds which were used without furtherpurification.

Step I:tert-Butyl(3aS,4S,5R,7aS)-4-(4-fluorophenyl)-5-hydroxyoctahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aR)-4-(4-fluorophenyl)-5-hydroxy-octahydro-2H-isoindole-2-carboxylate

To a solution of 7.5 g (31.9 mmol) of the intermediate of step H in drymethylene chloride under nitrogen atmosphere at RT was added 9.0 g (41.5mmol) of ditert-butyl dicarbonate. The resulting mixture was stirred atRT for 16 hr then the solvent evaporated under vacuum. The resultingmixture was dissolved in methanol and 5.0 N aq. NaOH was added. Theresulting mixture was stirred for 2 hr and the methanol removed undervacuum. The aqueous residue was diluted with EtOAc, transferred to aseparatory funnel and the organic layer separated. The aqueous layer wasextracted with an additional portion of EtOAc. The combined organiclayers were washed with 50 mL brine, dried over magnesium sulfate,filtered and the solvent evaporated under vacuum. The residue waspurified by flash column chromatography on silica gel eluting withEtOAc/hexanes (1/4) to give 2.8 g of the racemic title compounds. ¹H-NMR(CDCl₃): δ: ¹H-NMR (CDCl₃): δ ¹H-NMR (CDCl₃): δ 7.22 (2H, m), 7.07 (2H,m), 3.73 (1H, m), 3.48-3.33 (2H, m), 3.21-3.10 (2H, m), 2.51 (1H, m),2.18 (1H, t, J=10.7 Hz), 2.25 (1H, m), 1.98 (1H, m), 1.97-1.85 (1H, m),1.63 (1H, m), 1.51-1.40 (1H, m), 1.49, 1,43 (9H, two singlets). Alsoisolated was a minor amount of the mixture of cis alcohol (less polar):tert-butyl (3aR,4R,5R,7aR)-4-(4-fluorophenyl)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate andtert-butyl(3aS,4S,5S,7aS)-4-(4-fluorophenyl)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate.¹H-NMR (CDCl₃): δ: 7.25 (2H, m), 7.05 (2H, m), 3.95 (1H, m), 3.50-3.20(3H, m), 3.08, 2.95 (1H, two doublets, J=14.3 Hz), 2.77 (1H, m),2.65-2.55 (2H, m), 2.15 (1H, m), 1.82 (2H, m), 1.58 (1H, m), 1.45, 1.40(9H, two singlets).

Step J:tert-Butyl(3aS,4S,5R,7aS)-5-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-4-(4-fluorophenyl)-octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aR)-5-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of 0.09 g (0.26 mmol) of the intermediate of step I in drymethylene chloride under nitrogen atmosphere at RT was added 0.089 g(0.32 mmol) of 3,5-bis(trifluoromethyl)-benzoyl chloride, 0.07 mL TEAand a catalytic amount of DMAP. The resulting mixture was stirred at RTfor 2 hr then transferred to a separatory funnel, washed with sat. aq.NaHCO₃, aq. KHSO₄, and brine. The combined organic layers dried overmagnesium sulfate, filtered and the solvent evaporated under vacuum toafford 0.15 g of the crude title compounds which were used withoutfurther purification. ¹H-NMR (CDCl₃): δ: 8.63 (1H, s), 8.19 (2H, s),7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m), 3.59-3.43 (2H, m), 3.30-3.20(2H, m), 2.83 (1H, t, J=12.7 Hz), 2.62 (1H, m), 2.43 (1H, m), 2.20 (1H,m), 2.02 (1H, m), 1.90-1.70 (2H, m), 1.55, 1.47 (9H, two singlets).

Step K:tert-Butyl(3aS,4S,7aS)-5-({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}oxy)-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aR)-5-({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}oxy)-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of 0.15 g (0.26 mmol) of the intermediate of step J in dryTHF under nitrogen atmosphere at 0° C. was added 2 mL of a 0.5 Msolution of Tebbe reagent in toluene. The resulting mixture was stirredat 0° C. for 0.5 hr then carefully quenched by the dropwise addition of0.5 mL water, then 0.5 mL of 5.0 N aq. NaOH. The resulting suspensionwas diluted with ethyl acetate, stirred at RT for 0.5 hr and the solidsfiltered. The resulting filtrate stirred with 0.5 mL of 5.0 N aq. NaOHfor 16 hr and the solids filtered through a pad of filter aid. Thesolvent was evaporated under vacuum to give the crude title compoundswhich were used without further purification. ¹H-NMR (CDCl₃): δ: 7.73(1H, s), 7.55 (2H, s), 7.30-7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s),4.37 (1H, s), 4.25 (1H, m), 3.55-3.30 (3H, m), 3.27-3.15 (2H, m), 2.81(1H, t, J=12.7 Hz), 2.60 (1H, m), 2.40-30 (2H, m), 1.98 (1H, m), 1.83(1H, m), 1.55, 1.47 (9H, two singlets).

Step L:tert-Butyl(3aS,4S,5R,7aS)-5-{1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aR)-5-{1S-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylateandtert-Butyl(3aS,4S,5R,7aS)-5-{1S-[3,5-bis(trifluoromethyl)phenyl]-ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylatetert-butyl(3aR,4R,5S,7aR)-5-{1R-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

The intermediate of step G was hydrogenated at 50 PSI hydrogen over 10%by weight of 110% Pd—C in ethanol for 16 hr at RT. The catalyst wasfiltered and the solvent of the filtrate was evaporated under vacuum togive the crude title compounds which were purified by prep TLC elutingwith EtOAc/hexanes (1/3) to afford the two diastereomers. The less polar(the major) isomer, ¹H-NMR (CDCl₃): δ: 7.73 (1H, s), 7.58 (2H, s), 7.25(2H, m), 7.10 (2H, m), 4.05 (1H, m), 3.23-3.30 (3H, m), 3.20-3.07 (2H,m), 2.55 (1H, t, J=10.3 Hz), 2.45 (1H, m), 2.33 (1H, m), 2.20-1.55 (3H,m), 1.50, 1.43 (9H, two singlets), 0.95 (3H, d, J=6.9 Hz), 1.0-0.82 (1H,m). The minor isomer, ¹H-NMR (CDCl₃): δ 7.70 (1H, s), 7.20 (2H, s), 6.95(2H, m), 6.87 (2H, m), 4.45 (1H, m), 3.40 (1H, m), 3.27 (1H, m),3.15-3.05 (2H, m), 2.47 (2H, t, J=11.2 Hz), 2.15 (2H, m), 1.93 (1H, m),1.75 (1H, m), 1.62 (1H, m), 1.50 (1H, m), 1.50, 1.45 (9H, s), 1.30 (3H,two doublets, J=6.0 Hz).

Step M:(3aR,4R,5S,7aR)-5-{1(S)-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-1H-isoindoleand(3aS,4S,5R,7aS)-5-{1(R)-[3,5-bis(Trifluoromethyl)phenyl]-ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole

The less polar major diastereomer of intermediate Step L was dissolvedin dry methylene chloride and treated with anisole and TFA at RT for 2hr. The solvent was evaporated under vacuum and residue was taken up inEtOAc. The solution was washed with aq. NaOH, then brine, dried overdrying agent and filtered. The solvent was evaporated under vacuum togive the crude title compounds. ¹H-NMR (CDCl₃): δ: 7.77 (1H, s), 7.60(2H, s), 7.28 (2H, m), 7.12 (2H, t, J=8.2 Hz), 4.07 (1H, m), 3.35 (1H,m), 3.22-3.10 (2H, m), 3.00 (1H, m), 2.85 (1H, d, J=11.3 Hz), 2.65 (1H,t, J=11.3 Hz), 2.50 (1H, m), 2.40 (1H, m), 1.87-1.68 (2H, m), 1.53 (1H,m), 1.30 (1H, m), 0.95 (3H, d, J=6.0 Hz).

EXAMPLE 2

(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindoleStep A:(3aS,4S,5R,7aS)-2-Benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-oland(3aR,4R,5S,7aR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol

Starting with 3.5 g of the racemic mixture of(3aS,4S,5R,7aS)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-oland(3aR,4R,5S,7aR)-2-benzyl-4-(4-fluorophenyl)octa-hydro-1H-isoindol-5-ol(intermediate of Example 1, step G) was separated by chiral HPLC usingCHIRACEL AD column eluting with hexanes/EtOH (9/1) to afford the firsteluting isomer(3aS,4S,5R,7aS)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-oland the second eluting isomer(3aR,4R,5S,7aR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol.

Step B:tert-Butyl(3aR,4R,5S,7aR)-4-(4-fluorophenyl)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate

To a solution of 5.36 g (15.8 mmol) of the second eluting isomer(3aR,4R,5S,7aR)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol(intermediate of step A) in 80 mL EtOH was added 4.31 g (19.7 mmol) ofditert-butyl dicarbonate and 0.5 g of 10% Pd—C. The resulting mixturewas hydrogenated at 50 PSI hydrogen for 16 hr at RT. The catalyst wasfiltered and 5 mL of 5.0 N aq. NaOH was added. The solvent wasevaporated under vacuum. The aqueous residue was diluted with EtOAc,transferred to a separatory funnel, washed with brine, dried over dryingagent, filtered and the solvent evaporated under vacuum. The residue waspurified by flash column chromatography on silica gel eluting withEtOAc/hexanes (1/4) to give the title compound. ¹H-NMR (CDCl₃): δ: 7.22(2H, m), 7.07 (2H, m), 3.73 (1H, m), 3.48-3.33 (2H, m), 3.21-3.10 (2H,m), 2.51 (1H, m), 2.18 (1H, t, J=10.7 Hz), 2.25 (1H, m), 1.98 (1H, m),1.97-1.85 (1H, m), 1.63 (1H, m), 1.51-1.40 (1H, m), 1.49, 1,43 (9H, twosinglets).

Step C:tert-Butyl(3aR,4R,5S,7aR)-5-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

To a solution of 4.75 g (14.0 mmol) of the intermediate of step B in drymethylene chloride under nitrogen atmosphere at RT was added 4.71 g(17.0 mmol) of 3,5-bis(trifluoromethyl)benzoyl chloride, 2.4 mL (17.3mmol) TEA and a catalytic amount of DMAP. The resulting mixture wasstirred at RT for 2 hr then transferred to a separatory funnel, washedwith saturated. aq. NaHCO₃ and brine. The combined organic layers driedover magnesium sulfate, filtered and the solvent evaporated under vacuumto afford the crude title compound which was used without furtherpurification. ¹H-NMR (CDCl₃): δ: 8.63 (1H, s), 8.19 (2H, s), 7.25 (2H,m), 7.00 (2H, m), 5.22 (1H, m), 3.59-3.33 (2H, m), 3.30-3.20 (2H, m),2.83 (1H, t, J=12.7 Hz), 2.62 (1H, m), 2.43 (1H, m), 2.20 (1H, m), 2.02(1H, m), 1.90-1.70 (2H, m), 1.55, 1.47 (9H, two singlets).

Step D:tert-Butyl(3aR,4R,5S,7aR)-5-({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}oxy)-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

To a solution 9.5 g (14.0 mmol) of the crude intermediate of step C indry THF under nitrogen atmosphere at 0° C. was added 66 mL (33 mmol.) ofa 0.5 M solution of Tebbe reagent in toluene. The resulting mixture wasstirred at 0° C. for 2 hr then carefully quenched by the dropwiseaddition of 7.5 mL water, then 7.5 mL of 5.0 N aq. NaOH. The resultingsuspension was stirred at RT for 0.5 hr and the solids filtered. Theresulting filtrate stirred with 5 mL of 5.0 N aq. NaOH for 16 hr and thesolids filtered through filter aid. The solvent was evaporated undervacuum and the residue purified by column chromatography eluting withEtOAc/hexanes (1/3) to give the title compound. ¹H-NMR (CDCl₃): δ: 7.73(1H, s), 7.55 (2H, s), 7.30-7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s),4.37 (1H, s), 4.25 (1H, m), 3.55-3.30 (3H, m), 3.27-3.15 (2H, m), 2.81(1H, t, J=12.7 Hz), 2.60 (1H, m), 2.40-30 (2H, m), 1.98 (1H, m), 1.83(1H, m), 1.55, 1.47 (9H, two singlets)

Step E: tert-butyl(3aR,4R,5S,7aR)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

A solution of 10.2 g of the crude intermediate of step D in ethanol washydrogenated at 50 PSI hydrogen over ˜1 g of 10% Pd—C for 3 hr at RT.The catalyst was filtered and the solvent of the filtrate was evaporatedunder vacuum to give the crude title compounds which were purified bycolumn chromatography eluting with EtOAc/hexanes (2/3) to afford 8.9 g(15.5 mol) the two diastereomers with the major (S) diastereomer. Thismixture was taken up in ˜150 mL dry THF under nitrogen atmosphere andtreated with 80 mL (80 mmol) of a 1.0 M solution of potassiumtert-butoxide in THF. The resulting mixture was heated at 40° C. for 1hr, cooled to RT and quenched by the addition of water. The mixture wasdiluted with EtOAc, transferred to a separatory funnel, washed withbrine, dried over drying agent, filtered and the solvent evaporatedunder vacuum. The residue was purified by flash column chromatography onsilica gel eluting with EtOAc/hexanes (1/3) to give the less polartert-butyl(3aR,4R,5S,7aR)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octa-hydro-2H-isoindole-2-carboxylateand the more polar tert-butyl(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate.¹H-NMR (CDCl₃): δ: of the less polar isomer: δ: 7.73 (1H, s), 7.58 (2H,s), 7.25 (2H, m), 7.10 (2H, m), 4.05 (1H, m), 3.23-3.30 (3H, m),3.20-3.07 (2H, m), 2.55 (1H, t, J=10.3 Hz), 2.45 (1H, m), 2.33 (1H, m),2.20-1.55 (3H, m), 1.50, 1.43 (9H, two singlets), 0.95 (3H, d, J=6.9Hz), 1.0-0.82 (1H, m). ¹H-NMR (CDCl₃) of the more polar isomer: 7.71(1H, s), 7.20 (2H, s), 6.97 (2H, m), 6.85 (2H, m), 4.47 (1H, m),3.43-3.03 (4H, m), 2.47 (2H, m), 2.15 (2H, m), 1.92 (1H, t, J=10.5 Hz),1.80-1.57 (3H, m), 1.50, 1.43 (9H, two singlets), 1.30 (3H, d, J=6.9Hz).

Step F:(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindolehydrochloride salt

The more polar diastereomer of intermediate Step E (1.5 g, 2.6 mmol) wasdissolved in ˜20 mL 4 N HCl in dioxane and stirred at RT for 2 hr. Thesolvent was evaporated under vacuum and residue was taken up in EtOAc.The solution was washed with aq. NaOH, then brine, dried over dryingagent and filtered. The solvent was evaporated under vacuum to give thecrude title compound. Treatment with HCL in dioxane affirded the HClsalt ¹H-NMR (CDCl₃): δ: 7.75 (1H, s), 7.37 (2H, s), 7.13 (2H, m), 6.87(2H, t, J=8.5 Hz), 4.63 (1H, q, 6.5 Hz), 3.45 (1H, td, J=4 Hz, J₂=11.9Hz), 3.17 (1H, m), 3.10 (1H, dd, J₁=6.5 Hz, J₂=9.5 Hz), 2.90 (1H, J=12.7Hz), 2.57 (2H, m), 2.47 (1H, t, J=9.5 Hz), 2.25 (1H, m), 1.98 (2H, m),1.68 (1H, m), 1.10 (3H, d, 6.5 Hz). MS: (MH)⁺ 475.9.

EXAMPLE 3

(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-2-methyloctahydro-1H-isoindoleStep A:(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-2-methyloctahydro-1H-isoindole

To a solution of 30 mg (0.063 mmol) of(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole(Example 2) in ˜2 mL methanol was added ˜20 mg (excess) aq. formaldehydeand 40 mg sodium acetate. The resulting mixture was stirred at RT for 10min then 20 mg of NaBH₄ was added. The resulting mixture was stirred atRT for 1 hr then water was added. The methanol was evaporated undervacuum and residue extracted with ether (2×25 mL). The combined extractswere dried over drying agent, filtered and the solvent was evaporatedunder vacuum. The residue was purified by prep TLC eluting withEtOAc/MeOH (9/1) to give the title compound. ¹H-NMR (CDCl₃): δ: ppm.7.68 (1H, s), 7.23 (2H, s), 7.02 (2H, m), 6.87 (2H, m), 4.45 (1H, m),3.27 (1H,), 2.78-2.65 (2H, m), 2.57 (2H, m), 2.45-2.30 (3H, m),2.23-2.12 (2H, m), 1.98 (1H, m), 1.83-1.68 (2H, m), 1.30 (3H, 6.2) MS:(MH)⁺ 489.9.

EXAMPLE 4

(3aS,4S,5R,7aS)-5-{(1S)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-1H-isoindoleStep A:tert-Butyl(3aS,4S,5R,7aS)-4-(4-fluorophenyl)-5-hydroxyoctahydro-2H-isoindole-2-carboxylate

The title compound was prepared from of(3aS,4S,5R,7aS)-2-benzyl-4-(4-fluorophenyl)octahydro-1H-isoindol-5-ol(the first eluting isomer of Example 2 step A) according to theprocedure for Example 2, step B). ¹H-NMR (CDCl₃): δ: 7.22 (2H, m), 7.07(2H, m), 3.73 (1H, m), 3.48-3.33 (2H, m), 3.21-3.10 (2H, m), 2.51 (1H,m), 2.18 (1H, t, J=10.7 Hz), 2.25 (1H, m), 1.98 (1H, m), 1.97-1.85 (1H,m), 1.63 (1H, m), 1.51-1.40 (1H, m), 1.49, 1,43 (9H, two singlets).

Step B:tert-Butyl(3aS,4S,5R,7aS)-5-{[3,5-bis(trifluoromethyl)benzoyl]oxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

The title compound was prepared from the intermediate of step Aaccording to the procedure for Example 2, step C. ¹H-NMR (CDCl₃): δ:8.63 (1H, s), 8.19 (2H, s), 7.25 (2H, m), 7.00 (2H, m), 5.22 (1H, m),3.59-3.433 (2H, m), 30-3.20 (2H, m), 2.83 (1H, t, J=12.7 Hz), 2.62 (1H,m), 2.43 (1H, m), 2.20 (1H, m), 2.02 (1H, m), 1.90-1.70 (2H, m), 1.55,1.47 (9H, two singlets).

Step C:tert-Butyl(3aS,4S,5R,7aS)-5-({1-[3,5-bis(trifluoromethyl)phenyl]vinyl}oxy)-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

The title compound was prepared from the intermediate of step Baccording to the procedure for Example 2, step D. ¹H-NMR (CDCl₃): δ 7.73(1H, s), 7.55 (2H, s), 7.30-7.18 (2H, m), 7.03 (2H, m), 4.67 (1H, s),4.37 (1H, s), 4.25 (1H, m), 3.55-3.30 (3H, m), 3.27-3.15 (2H, m), 2.81(1H, t, J=12.7 Hz), 2.60 (1H, m), 2.40-2.30 (2H, m), 1.98 (1H, m), 1.83(1H, m), 1.55, 1.47 (9H, two singlets).

Step D:tert-Butyl(3aS,4S,5R,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylateand tert-butyl(3aS,4S,5R,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate

The title compounds were prepared from the intermediate of step Caccording to the procedure for Example 2, step E. ¹H-NMR (CDCl₃): δ: theless polar isomer, δ: 7.73 (1H, s), 7.58 (2H, s), 7.25 (2H, m), 7.10(2H, m), 4.05 (1H, m), 3.23-3.30 (3H, m), 3.20-3.07 (2H, m), 2.55 (1H,t, J=10.3 Hz), 2.45 (1H, m), 2.33 (1H, m), 2.20-1.55 (3H, m), 1.50, 1.43(9H, two singlets), 0.95 (3H, d, J=6.9 Hz), 1.0-0.82 (1H, m). ¹H-NMR(CDCl₃) of the more polar isomer: 7.71 (1H, s), 7.20 (2H, s), 6.97 (2H,m), 6.85 (2H, m), 4.47 (1H, m), 3.43-3.03 (4H, m), 2.47 (2H, m), 2.15(2H, m), 1.92 (1H, t, J=10.5 Hz), 1.80-1.57 (3H, m), 1.50, 1.43 (9H, twosinglets), 1.30 (3H, d, J=6.9 Hz).

Step E:(3aS,4S,5R,7aS)-5-{(1S)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole

The title compound was prepared from of tert-butyl(3aS,4S,5R,7aS)-5-{(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindole-2-carboxylate(step D) according to the procedure for Example 2, step F. The morepolar isomer, ¹H-NMR (CDCl₃): δ: 7.68 (I H, s), 7.20 (2H, s), 7.05 (2H,m), 6.87 (2H, t, J=8.2 Hz), 4.27 (1H, m), 3.28 (1H, m), 3.20-3.05 (2H,m), 2.88 (1H, m), 2.72 (1H, d, J=11.7 Hz), 2.58 (1H, t, J=11.9 Hz), 2.40(1H, m), 2.20 (1H, m), 2.10 (1H, m), 1.92 (1H, m), 1.83 (1H, m), 1.60(1H, m), 1.30 (3H, d, J=6.0 Hz). MS: (MH)⁺ 475.9.

EXAMPLE 5

3-[(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one

To a solution of 12.3 mg (0.26 mmol) of(3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}4-(4-fluorophenyl)octahydro-1H-isoindole(Example 2) in ˜2 mL dry toluene was added 2.7 mg (0.028 mmol)cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. Theresulting mixture was heated at reflux for 16 hr. The solvent wasremoved vacuum and the residue was purified by prep TLC eluting withEtOAc/MeOH (95/5) to afford the title compound. ¹H-NMR (CDCl₃): δ: 7.73(1H, s), 7.20 (2H, s), 7.03-6.90 (2H, m), 4.98, 4.80 (1H, s), 4.50 (1H,m), 3.62-3.18 (2H, m), 3.30-3.18 (3H, m), 3.15, 2.97 (1H, d, J=11.2 Hz),2.68 (2H, m), 2.55-2.40 (4H, m), 2.17 (1H, m), 2.20 (1H, m), 2.00 (1H,m), 1.85 (1H, m), 1.62 (1H, m), 1.33 (3H, d, J=6.2 Hz). MS: (MH)⁺ 556.0.

EXAMPLE 6

(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-1H-isoindoleStep A: Diethyl4-{[tert-butyl(dimethyl)silyl]oxy}-3-(4-fluorophenyl)cyclohex-4-ene-1,2-dicarboxylate

To a solution of 37 g (˜80% pure, 133.1 mmol, 1 equiv.) of 1E and1Z-tert-butyl{[1-(4-fluorobenzylidene)prop-2-en-1-yl]oxy}dimethylsilane(Example 1, step C) and 17 mL (18 g, 104.6 mmol)diethyl(2E)-but-2-enedioate in 200 mL xylenes under nitrogen atmospherewas heated at 160° C. for 5 hr then cooled to RT. The solvent wasevaporated under vacuum to give an oil which was used without furtherpurification.

Step B: RacemicDiethyl(1S,2S,3R)-3-(4-fluorophenyl)-4-oxocyclohexane-1,2-dicarboxylateanddiethyl(1R,2R,3S)-3-(4-fluorophenyl)-4-oxocyclohexane-1,2-dicarboxylate

To a solution of the above intermediate in 30 mL acetonitrile undernitrogen atmosphere at RT in a plastic reaction flask was added 200 mL(500 mmol) of a 2.5 M solution of HF in acetonitrile. The resultingmixture was stirred at RT for 24 hr. The reaction mixture was added to amixture of 125 mL 5.0 N aq. NaOH and 100 g ice, then stirred at RT for 5min. The resulting mixture was diluted with 300 mL ether. The resultingmixture was transferred to a separatory funnel and the organic layerseparated. The aqueous layer was saturated with NaCl then extracted withan additional portion of ether. The combined organic layer was washedwith brine, dried over drying agent, filtered and the solvent evaporatedunder vacuum to give 40.8 g of the title compounds. ¹H-NMR (CDCl₃): δ:7.10 (2H, m), 7.05 (2H, m), 4.23-4.15 (2H, m), 3.90-3.80 (3H, m), 3.32(1H, td, J=13.0 Hz, J₂=4.0 Hz), 3.21 (1H, t, J=12.9 Hz), 2.68 (2H, m),2.55 (1H, m), 2.07 (1H, m), 1.30 (3H, t, J=7.2 Hz), 0.85 (3H, t, J=7.2Hz).

Step C: Racemicdiethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylateanddiethyl(1R,2R,3S,4R)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate

To a solution 40.2 g (119.3 mmol) of the intermediate of step B in 150mL ethanol under nitrogen atmosphere at −78° C. was added 4.1 g (108.5mmol) NaBH₄ powder. The resulting mixture was stirred at −78° C. for 0.5hr then at RT for 2 hr. The reaction mixture was carefully quenched bythe addition of 30 mL water and carefully acidified with 2N aq. HCl. Thesolvent was evaporated under vacuum. The residue dissolved in ether,transferred to a separatory funnel, washed with sat. aq. NaHCO₃ andbrine, dried over drying agent, filtered and the solvent evaporatedunder vacuum to give the crude title compounds which were purified inthe next step. ¹H-NMR (CDCl₃): δ: 7.25 (2H, m), 7.05 (2H, t, J=8.2 Hz),4.20-4.05 (2H, m), 3.85-3.72 (3H, m), 2.85 (2H, m), 2.70 (1H, t, J=7.8Hz), 2.25 (2H, m), 1.70 (1H, m), 1.60 (1H, m), 1.25 (3H, t, J=7.2 Hz),0.85 (3H, t, J=7.2 Hz).

Step D:Diethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate

Starting with 21 g of the racemic mixture ofdiethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylateanddiethyl(1R,2R,3S,4R)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate(step C) was separated by preparative chiral HPLC using CHIRACEL ADcolumn eluting with heptanes/i-PrOH (9/1) to afford 9.09 g of thedesired first eluting isomerdiethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate.

Step E:(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate

A solution of 25.82 g (100 mmol) of(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol in 200 mL dry diethylether under nitrogen atmosphere was cooled in an ice/water bath. Neat 3mL (20 mmol, 0.2 equiv) DBU was added to the reaction flask then themixture was stirred at 0° C. for ten min. Slowly 15 mL (150 mmol, 1.5equiv.) trichloroacetonitrile was added dropwise over 15 min. Thereaction was stirred at 0° C. for 2 hr. during which time it became deepyellow in color. The volatiles were removed under vacuum using a coolbath (<35° C.) to give a pale brown mobile liquid which was purified bycolumn chromatography on silica gel (3″×10″ pad) in two batches elutingwith hexanes/EtOAc (9/1) then hexanes/EtOAc (4/1). The product fractionswere combined and the solvent removed under vacuum to give 37.5 g of thetitle compound as a pale yellow oil. ¹H-NMR (CDCl₃): δ: 1.74 (3H, d,J=6.5 Hz), 6.07 (1H, q, J=6.5 Hz), 7.82 (1H, s), 7.86 (2H, s), 8.40 (1H,br. s) ppm.

Step F:Diethyl(1S,2S,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate

To a solution of 9.09 g (26.9 mmol) of the first eluting isomerdiethyl(1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate(step D) and 21.5 g (53.5 mmol) of(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate(step E) in 250 mL of cyclohexane/1,2-chloroethane (3/1) under nitrogenatmosphere at −5° C. was added 0.51 mL (3.58 mmol) of 54% HBF₄ in ether.The reaction mixture was stirred at −5° C. to at 0° C. for 2 hr thendiluted with ether. The mixture was washed with sat. aq. NaHCO₃. Theorganic layer was dried over drying agent, filtered and the solventevaporated under vacuum. The residue was purified by flash columnchromatography on silica gel eluting with EtOAc/hexanes (1/4) to give9.2 g of the title compound as an oil. ¹H-NMR (CDCl₃): δ: δ: 7.70 (1H,s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, t, J=8.5 Hz), 4.43 (I H, q,J=6.0 Hz), 4.20-4.10 (2H, m), 3.80-3.73 (2H, m), 3.36 (1H, m), 2.90-2.76(2H, m), 2.40 (1H, m), 2.28 (1H, m), 1.63-1.55 (2H, m), 1.33 (3H, d,J=6.0 Hz), 1.25 (3H, t, J=7.2 Hz), 0.82 (3H, t, J=7.2 Hz). Unreactedstarting alcohol could be recovered by flushing the column with EtOAcand reused in the above reaction.

Step G:[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol

To a solution of 9.2 g (15.9 mmol)diethyl(1S,2S,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-dicarboxylate(step F) in 100 mL THF under nitrogen atmosphere at RT was added 2 g(112.4 mmol, excess) LiBH₄ powder. The resulting mixture was heated at68° C. for 2 hr then cooled to RT. The reaction mixture was carefullyquenched by the addition of 30 mL water, then extracted with EtOAc. Thecombined organic extracts were dried over drying agent, filtered and thesolvent evaporated under vacuum to give 7.5 g of the crude titlecompound as an oil which was used without further purification. ¹H-NMR(CDCl₃): δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.87 (2H, t, J=8.2Hz), 4.20 (1H, q, J=6.0 Hz), 3.78 (1H, m), 3.67 (1H, m), 3.52 (1H, m),3.30-3.20 (2H, m), 2.58 (1H, t, J=11.9 Hz), 2.32 (1H, m), 1.87 (1H, m),1.65 (1H, m), 1.58-1.35 (3H, m), 1.30 (3H, t, J=6.0 Hz).

Step H:[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene)dimethanesulfonate

To a solution of 1.82 g (3.7 mmol)[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]dimethanol(step G) in 50 mL methylene chloride cooled to −5° C. in an ice/saltbath was added 1.0 mL (3.5 equiv.) methane-sulfonyl chloride; 2.1 mL (4equiv.) TEA and 44 mg (0.1 equiv.) DMAP. The reaction mixture wasstirred at −5° C. for 30 min then quenched at that temperature by theaddition of 20 mL sat. aq. NaHCO₃. The mixture was warmed to RT. Theorganic layer was separated and the aqueous layer extracted withadditional 50 mL methylene chloride. The combined organic layer waswashed with 20 mL 2N aq. HCl, 30 mL sat. aq. NaHCO₃, brine, dried overMgSO₄ drying agent, filtered and the solvent evaporated under vacuum togive the title compound as an oil which was used without furtherpurification.

Step I:(3aR,4R,5S,7aS)-2-Benzyl-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole

In a pressure tube was placed a solution of crude[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(4-fluorophenyl)cyclohexane-1,2-diyl]di(methylene)dimethanesulfonate (step H) in ˜20 mL ethanol and 1.2 mL (˜3 equiv.)benzylamine. The pressure tube was sealed and heated at 150° C. in anoil bath for 3 hr. The tube was cooled to RT and opened. The resultingmixture was transferred to a round bottom flask and the solvent removedunder vacuum. The residue was diluted with 100 mL EtOAc, washed with 20mL 5N aq. NaOH, dried over MgSO₄ drying agent, filtered and the solventwas evaporated under vacuum. The residue was purified by flash columnchromatography on silica gel eluting with EtOAc to give 1.6 g of thetitle compound. ¹H-NMR (CDCl₃): δ: 7.35-7.20 (5H, m), 7.50 (2H, s), 6.97(2H, m), 6.85 (2H, t, J=8.2 Hz), 4.42 (1H, t, J=6.0 Hz), 3.75 (2H, d,J=13.4 Hz), 3.50 (2H, d, J=13.4 Hz), 3.30 (1H, m), 2.96 (1H, m), 2.52(3H, m), 2.19 (2H, m), 1.98 (1H, m), 1.97 (1H, m), 1.86 (2H, m), 1.57(1H, m), 1.33 (3H, t, J=6.0 Hz), 1.30 (1H, m). MS: (MH)⁺ 566.0.

Step J:(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole

To a solution of(3aR,4R,5S,7aS)-2-benzyl-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole(step H) in ˜50 mL EtOH was added 0.2 g (20% by weight) of 10%Pd(OH)₂—C. The reaction mixture was hydrogenated at 50 PSI for 16 hr atRT. The catalyst was filtered and the solvent of the filtrate wasevaporated under vacuum to give the title compound. ¹H-NMR (CDCl₃): δ:7.70 (1H, s), 7.20 (2H, s), 6.95 (2H, m), 6.87 (2H, t, J=8.5 Hz), 4.42(1H, q, J=6.5 Hz), 3.55 (1H, m), 3.30 (1H, m), 3.10-2.95 (2H, m), 2.83(1H, m), 2.70 (1H, m), 2.52 (1H, m), 2.40 (1H, m), 2.10 (1H, m), 1.97(2H, m), 1.80 (1H, m), 1.33 (3H, d, J=6.2 Hz). MS: (MH)⁺ 476.1.

EXAMPLE 7

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one

To a solution of 0.73 g (1.5 mmol) of(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole(Example 6) in 25 mL dry toluene was added 0.166 g (1.7 mmol)cyclopentane-1,3-dione and 0.03 g (0.15 mmol) of PTSA. The resultingmixture was heated at reflux for 2 hr. The solvent was removed undervacuum and the residue was purified by prep TLC eluting with CHCl₃/2NNH₃ in MeOH (9/1) to afford 0.49 g the title compound. The compoundcould be further purified by chiral HLPC on CHIRACEL AD column elutingwith hexanes/EtOH (9/1). The compound could be crystallized(mp=216.5-217.5° C.) from hexanes/EtOAc or hexanes/EtOH. ¹H-NMR (CDCl₃):δ: 7.71 (1H, s), 7.23 (2H, s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz),4.89, 4.48 (1H, s), 4.47 (1H, m), 3.71, 3.48 (1H, m), 3.35 (1H, m),3.28-3.17 (1H, m), 2.95 (1H, m), 2.95, 2.81 (1H, m), 2.68 (2H, m), 2.45(2H, m), 2.37 (2H, m), 2.15 (1H, m), 1.93 (2H, m), 1.60 (1H, m), 1.38(1H, m), 1.36 (3H, t, J=6.0 Hz). MS: (MH)⁺ 556.0.

EXAMPLE 8

(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-N-methyloctahydro-2H-isoindole-2-carboxamide

To a solution of ˜20 mg (0.042 mmol) of(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole(Example 6) in ˜2 mL dry methylene chloride at RT was added severaldrops of methylisocyanate. The resulting mixture was stirred at RT 2 hr.Several drops of 2 N aq. NaOH were added to the reaction mixture. Theorganic layer was separated, dried over drying agent, filtered and thesolvent removed under vacuum. The residue was purified by pre TLCeluting with EtOAc and the major product band isolated. The residue wastaken up in EtOAc and the solids filtered. The solvent of the filtratewas removed under vacuum to afford the title compound. ¹H-NMR (CDCl₃):δ: 7.71 (1H, s), 7.23 (2H, s), 6.98 (2H, m), 6.85 (2H, m), 4.45 (1H, m),4.00 (1H, m), 3.68 (1H, m), 3.36 (1H, m), 3.08 (1H, m), 2.93 (1H, m),2.77 (3H, s), 2.55 (1H, m), 2.45 (1H, m), 2.10 (1H, d, J=12.5 Hz),2.00-1.70 (2H, m), 1.70-1.50 (1H, m), 1.30 (1H, m), 1.30 (3H, d, J=6.0Hz). MS: (MH)⁺ 533.5.

EXAMPLE 9

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]-5-hydroxycyclopent-2-en-1-one

To a solution of 20 mg (0.07 mmol) of3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one(Example 7) and 170 mg (0.39 mmol) MoOPH in ˜2 mL dry THF under nitrogenatmosphere at −78° C. was added ×0.076 mL (0.15 mmol) of 2.0 M solutionof KHMDS. The resulting mixture was stirred at −78° C. for 2 hr thenquenched by the addition of sat. aq. NH₄Cl. The mixture was extractedwith EtOAc. The combined organic extracts were washed with brine, driedover drying agent and filtered. The residue was purified by prep TLCeluting with CHCl₃/2N NH₃ in MeOH (9/1) to afford the title compound asa mixture of diastereomers. ¹H-NMR (CDCl₃): δ: 7.71 (1H, s), 7.23 (2H,s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz), 4.85, 4.71 (1H, s), 4.47 (1H,m), 4.20 (1H, m), 3.80-3.65 (1H, m), 3.37 (1H, m), 3.25-3.08 (1H, m),3.10-2.80 (3H, m), 2.58 (1H, m), 2.50-2.30 (1H, m), 2.15 (1H, m), 1.95(2H, m), 1.35 (3H, d, J=6.0 Hz). MS: (MH)⁺ 572.5. The diastereomers wereseparated by HPLC on CHIRACEL AS column eluting with hexanes/EtOH(85/15) to afford the individual diastereomers.

EXAMPLE 10

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]-4-hydroxycyclopent-2-en-1-oneStep A:4-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-4-ene-1,3-dione

The title compound was prepared from(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole(Example 6) and cyclopentane-1,2,4-trione according to the procedure ofExample 7. MS: (MH)⁺ 570.0

Step B:3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)-octahydro-2H-isoindol-2-yl]-4-hydroxycyclopent-2-en-1-one

The title compound was prepared as a mixture of diastereomers from theintermediate of step A according to the procedure of Example 6, step C(NaBH4 in methanol). ¹H-NMR (CDCl₃): rotamers; δ: 7.71 (1H, s), 7.23(2H, s), 7.00 (2H, m), 6.93 (2H, t, J=8.2 Hz), 4.88-4.65 (2H, m), 4.46(1H, m), 4.07 (0.5H, m), 3.83 (0.5H, m), 3.55 (1H, m), 3.35 (1H, m),3.28 (1H, m), 2.97 (2H, m), 2.92 (1H, m), 2.58 (1H, m), 2.43 (1H, m),2.25 (1H, m), 2.13 (1H, m), 2.05-1.85 (2H, m), 1.70-1.55 (2H, m), 1.30(3H, 2d, J=6.0 Hz). MS: (MH)⁺ 572.5 The diastereomers were separated byHPLC on CHIRACEL OD column eluting with hexanes/EtOH (85/15) to affordthe individual diastereomers.

EXAMPLE 11

3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-oneStep A: 2-(2-Methylphenyl)-N-methoxy-N-methylacetamide

The title compound was prepared from 2-(methylphenyl)acetic acidaccording to the procedure for Example 1, Step A. ¹H-NMR (CDCl₃): δ:7.23 (4H, m), 3.83 (2H, s), 3.65 (3H, s), 3.28 (3H, s), 2.36 (3H, s).

Step B: 1-(2-Methylphenyl)but-3-en-2-one

The title compound was prepared from the intermediate of step Aaccording the procedure of Example 1, step B. ¹H-NMR (CDCl₃): δ:7.24-7.11 (4H, m), 6.42 (1H, dd, J₁=14.2 Hz, J₂=11 Hz), 6.34 (1H, d,J=14.2 Hz), 5.81 (1H, d, J=11 Hz), 3.90 (2H, s) 2.26 (3H, s).

Step C: 1E and 1Ztert-butyl{[1-(2-Methylbenzylidene)prop-2-en-1-yl]oxy}dimethylsilane

The title compound was prepared from the intermediate of step Baccording to the procedure of Example 1, step C. ¹H-NMR (CDCl₃): δ:7.22-7.07 (4H, m), 6.40 (1H, dd, J₁=13.2 Hz, J₂=8.5 Hz), 5.85 (1H, s),5.54 (1H, d, J=13.2 Hz), 5.19 (1H, d, J=8.5 Hz) 2.28 (3H, s).

Step D: Diethyl4-{[tert-butyl(dimethyl)silyl]oxy}-3-(2-methylphenyl)cyclohex-4-ene-1,2-dicarboxylate

The title compound was prepared from the intermediate of step Caccording to the procedure of Example 6, step A and was used withoutfurther purification.

Step E: Racemicdiethyl(1S,2S,3R)-3-(2-methylphenyl)-4-oxocyclohexane-1,2-dicarboxylateanddiethyl(1R,2R,3S)-3-(2-methylphenyl)-4-oxocyclohexane-1,2-dicarboxylate

The title compounds were prepared from the intermediate of step Daccording to the procedure of Example 6, step B. ¹H-NMR (CDCl₃): δ:7.26-7.09 (4H, m), 4.23-4.12 (2H, m), 3.90-3.80 (3H, m), 3.32 (1H, td,J₁=13.0 Hz, J₂=4.0 Hz), 3.28 (1H, t, J=13 Hz), 2.67 (2H, m), 2.50 (1H,m), 2.24 (3H, s), 2.09 (1H, m), 1.25 (3H, t, J=7.2 Hz), 0.83 (3H, t,J=7.2 Hz).

Step F: Racemicdiethyl(1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylateanddiethyl(1R,2R,3S,4R)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate

The title compounds were prepared from the intermediate of step Eaccording to the procedure of Example 6, step C. ¹H-NMR (CDCl₃): δ:7.20-7.10 (4H, m), 4.15-4.07 (2H, m), 3.88-3.66 (3H, m), 3.09 (1H, t),2.83 (2H, m), 2.30 (3H, s), 2.24-2.15 (2H, m), 1.68 (1H, m), 1.57 (1H,m), 1.25 (3H, t, J=7.2 Hz), 0.83 (3H, t, J=7.2 Hz),

Step G:Diethyl(1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate

The racemic mixture ofdiethyl(1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylateanddiethyl(1R,2R,3S,4R)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate(step F) was separated by preparative chiral HPLC using CHIRACEL ADcolumn eluting with heptanes/i-PrOH (9/1) to afford the desired firsteluting isomerdiethyl(1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylateaccording to the procedure of Example 6, Step D.

Step H:Diethyl(1S,2S,3R,4S)-4-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-3-(2-methylphenyl)cyclohexane-1,2-dicarboxylate

The title compound was prepared from the first eluting isomerdiethyl(1S,2S,3R,4S)-3-(2-methylphenyl)-4-hydroxycyclohexane-1,2-dicarboxylate(step G) and(1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate(Example 6, step E) according to the procedure of Example 6, step F.¹H-NMR (CDCl₃): δ: 7.65 (1H, s), 7.15 (2H, s), 7.08-6.92 (4H, m), 4.25(1H, q, J=6.0 Hz), 4.20-4.10 (2H, m), 3.85-3.66 (2H, m), 3.42 (1H, m),3.21 (1H, t), 2.90-2.79 (2H, m), 2.35 (1H, m), 2.25 (1H, m), 2.22 (3H,s), 1.69-1.56 (2H, m), 1.30 (3H, d, J=6.0 Hz), 1.23 (3H, t, J=7.2 Hz),0.77 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered byflushing the column with EtOAc and reused in the above reaction.

Step I:[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-3-(2-methylphenyl)cyclohexane-1,2-diyl]dimethanol

The title compound was prepared from the intermediate of step Haccording to the procedure of Example 6, step G. ¹H-NMR (CDCl₃): δ: 7.64(1H, s), 7.16 (2H, s), 7.04-6.91 (4H, m), 4.24 (1H, q, J=6.0 Hz), 3.74(1H, m), 3.60 (1H, m), 3.48 (1H, m), 3.35-3.20 (2H, m), 2.90-2.70 (2H,m), 2.26 (1H, m), 2.21 (3H, s),1.85 (1H, m), 1.62 (1H, m), 1.56-1.42(3H, m), 1.28 (3H, t, J=6.0 Hz).

Step J:[(1S,2R,3R,4S)-4-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-3-(2-methylphenyl)cyclohexane-1,2-diyl]di(methylene)dimethanesulfonate

The title compound was prepared from the intermediate of Step Iaccording to the procedure of Example 6, step H and used without furtherpurification.

Step K:(3aR,4R,5S,7aS)-2-Benzyl-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole

The title compound was prepared from the intermediate step J andbenzylamine according to the procedure of Example 6, step I. ¹H-NMR(CDCl₃): δ: 7.64 (1H, s), 7.32-7.25 (5H, m), 7.18 (2H, s), 7.04-6.97(4H, m), 4.25 (1H, q, J=6.0 Hz), 3.75 (1H, d, J=13.4 Hz), 3.65 (1H, d,J=13.4 Hz), 3.40 (1H, m), 2.90 (2H, m), 2.54-2.30 (4H, m), 2.22 (3H, s),2.02-1.85 (3H, m), 1.61 (I H, m), 1.33 (3H, t, J=6.0 Hz), 1.30 (1H, m).

Step L:(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole

The title compound was prepared from the intermediate step K accordingto the procedure of Example 6, step J. ¹H-NMR (CDCl₃): δ: 7.64 (1H, s),7.18 (2H, s), 7.04-6.97 (4H, m), 4.25 (1H, q, J=6.5 Hz), 3.40 (1H, m),3.25 (1H, m), 2.90-2.75 (2H, m), 2.63 (1H, t), 2.44 (1H, t), 2.35 (1H,m), 2.22 (3H, s), 2.05 (1H, m), 1.86-1.72 (2H, m), 1.61 (1H, m),1.33-1.20 (5H, m).

Step M:3-[(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(Trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)-octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one

The title compound was prepared from(3aR,4R,5S,7aS)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(2-methylphenyl)octahydro-1H-isoindole(step L) and cyclopentane-1,3-dione according to the procedure ofExample 7. ¹H-NMR (CDCl₃): rotamers δ: 7.64 (1H, s), 7.18 (2H, s),7.04-6.97 (4H, m), 4.74, 4.53 (1H, s), 4.42 (1H, m), 3.68, 3.43 (1H, m),3.50 (1H, m), 3.06 (1H, m), 2.93 (2H, m), 2.86, 2.76 (1H, m), 2.57 (1H,m), 2.40 (2H, m), 2.28 (3H, s), 2.20 (1H, m), 2.17 (1H, m), 2.10-1.94(3H, m), 1.58 (1H, m), 1.40 (1H, m), 1.28 (3H, d, J=6.0 Hz). MS: (MH)⁺552.43

Using the procedures essentially comparable to those described above thecompounds of the following Examples were prepared.

parent ion Ex. # R¹ X (MH⁺) m/z 12

F 518.45 13

F 580.0 14

F 520.1 15

F 533.59

Using the procedures essentially comparable to those described above thecompounds of the following Examples were prepared.

parent ion Ex. # R¹ X (MH⁺) m/z 16

F 518.28 17 Me F 490.25 18

H 538.7 19

F 572.5 20

F 572.5 21

F 572.5 22

F 572.5 23

F 570.0 24

F 533.05 25

F 519.0

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

1-10. (canceled)
 11. A method for treating or preventing a disorder ofbladder function in a human patient in need of such treatment orprevention, comprising administering to the patient a therapeuticallyeffective amount of a compound of formula I:

wherein: R¹ is selected from the group consisting of: (1) hydrogen, (2)C₁₋₆alkyl, which is unsubstituted or substituted with halogen, hydroxylor phenyl, (3) cyclopentenone, which is unsubstituted or substitutedwith hydroxyl or methyl, (4) —(CO)—C₁₋₆alkyl, (5) —(CO)—NH₂, (6)—(CO)—NHC₁₋₆alkyl, and (7) —(CO)—N(C₁₋₆alkyl)(C₁₋₆alkyl); (1) hydrogen,(2) fluorine, and (3) methyl; and pharmaceutically acceptable saltsthereof and individual enantiomers and diastereomers thereof.
 12. Themethod according to claim 11 wherein the compound of formula I is

or a pharmaceutically acceptable salt thereof.
 13. The method accordingto claim 12 wherein the disorder of bladder function is cystitis. 14.The method according to claim 12 wherein the disorder of bladderfunction is bladder detrusor hyper-reflexia.
 15. The method according toclaim 12 wherein the disorder of bladder function is frequent urination.16. The method according to claim 12 wherein the disorder of bladderfunction is urinary incontinence.
 17. The method according to claim 12wherein the disorder of bladder function is overactive bladder with oneor more of the symptoms of urge urinary incontinence, urgency orfrequency.